A background reference on amphiphilic materials in which, e.g., a radionuclide or an MR active metal can be incorporated is e.g. V. Torchilin, Chemtech 1999, Volume 29, Number 11, 27-34. This paper refers to polychelating amphiphilic polymers. These are predominantly polymers based on poly-L-lysine comprising a hydrophilic fragment with multiple chelating groups and a relatively short, highly lipophilic phospholipid fragment. The latter serves to incorporate the polymer into liposomes and micelles.
The invention pertains to a different class of amphiphilic polymers, viz. those that are capable of self-assembly into polymersomes, micelles, or polymer-stabilized emulsions. These polymers can generally be described as block polymers comprising at least one hydrophilic block (A), preferably having a chain of more than 500 g/mole molecular weight, and at least one hydrophobic block (B), also in the form of a polymer block (i.e. not a lipid). These polymers can take the form of a block copolymer AB, of a triblock polymer ABA or BAB, or of any further block polymer having a terminal hydrophilic block and a terminal hydrophobic block, including polymers comprising a chain (C) having ambiguous solvent properties (i.e. neither hydrophilic nor hydrophobic), e.g. a block terpolymer ACB. In general, this will mean that the block C forms either a new hydrophilic block, together with block A, or a new hydrophobic block, together with Block B.
As a result of the presence of a hydrophilic and a hydrophobic block, amphiphilic polymers have the ability to form self-assembled structures. The most typical self-assembled structures are micelles and polymersomes as formed in aqueous environment. In either case, however, depending on the medium in which they are formed, either type of block (i.e. hydrophilic or hydrophobic) can form the inside or the outside. In micelles the inside comprises converging, inwardly pointing polymeric chains and the outside comprises diverging, outwardly pointing polymeric chains. In polymersomes, the self-assembled structure comprises a wall enclosing a cavity. The wall most typically, alike liposomes, is formed by a polymeric bilayer, in an aqueous medium having the hydrophobic blocks directed towards each other at the inside of the bilayer and the hydrophilic blocks at the inside of the cavity and at the outside surface of the polymersome.
As opposed to lipid vesicles (i.e. liposomes), polymersomes are chemically more stable, less leaky, less prone to interfere with biological membranes, and less dynamic due to their lower critical aggregation concentration. These properties result in less opsonisation and longer circulation times. On the other hand, liposomes offer the advantage that imaging agents or targeting moieties can easily be incorporated into the lipid layer. Liposomes can also be used very well as contrast agents, in which case they are provided e.g. with a paramagnetic label for MRI or a radionuclide for SPECT or PET.
Though liposomes offer a very versatile approach, a major limitation is the low degree of PEGylation, i.e. providing the surface with covalently attached poly (ethylene glycol). PEGylation is a known technique to mask entities, such as therapeutic proteins, when introduced into a person's body from the immune system of the person. This is believed to be based on a lower degree of opsonisation, as a result of which PEGylated surfaces are less prone to macrophage uptake. This serves to increase the circulation time of the PEGylated entity. For liposomes and other nanocarriers to be practically suitable, it is thus desired to similarly mask them, i.e. to providetealth, PEGylated nanocarriers.